Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis.
Proc Natl Acad Sci U S A
; 100(7): 4012-7, 2003 Apr 01.
Article
en En
| MEDLINE
| ID: mdl-12651943
The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1alpha interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4alpha in the liver, we show here that PGC-1alpha completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4alpha is absent. It is also shown that PGC-1alpha can induce genes of beta-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4alpha. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4alpha-binding sites that function robustly only when HNF4alpha is coactivated by PGC-1alpha. These data illustrate the involvement of PGC-1alpha in several aspects of the hepatic fasting response and show that HNF4alpha is a critical component of PGC-1alpha-mediated gluconeogenesis.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
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Factores de Transcripción
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Ayuno
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Receptores Citoplasmáticos y Nucleares
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Hepatocitos
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Gluconeogénesis
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Hígado
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2003
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos